Adjunctive Use of Apyrase to Fibrinolytic Therapy

腺苷三磷酸双磷酸酶辅助纤溶治疗

• 批准号: 8315704
• 负责人: RIDONG CHEN
• 金额: $ 72.96万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315704
• 关键词: Accounting; Acute; Acute myocardial infarction; Adenosine; Adverse event; Aftercare; Alteplase; Amino Acid Substitution; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Apyrase; Aspirin; Attenuated; Award; Bleeding time procedure; Blood Platelets; Blood Vessels; Blood flow; Canis familiaris; Cardiac; Cause of Death; Cell Line; Chinese Hamster Ovary Cell; Clinical; Coronary; Data; Developed Countries; Disease; Dose; Endotoxins; Enzymes; Event; Exhibits; Fibrinolysis; Fibrinolytic Agents; Goals; Hemorrhage; Hemostatic function; Heparin; Homeostasis; Hour; Human; Hypoxia; Incidence; Infarction; Injury; Investigational New Drug Application; Left Ventricular Function; Licensing; Maintenance; Marketing; Modeling; Morbidity - disease rate; Myocardial Infarction; Myocardial Reperfusion; Myocardial perfusion; Oryctolagus cuniculus; Outcome; Patients; Perfusion; Phase; Platelet Activation; Preparation; Procedures; Proteins; Recurrence; Regimen; Reperfusion Injury; Reporting; Risk; Safety; Site; Small Business Innovation Research Grant; Therapeutic; Thrombolytic Therapy; Thrombosis; Tissues; Toxic effect; adverse outcome; attenuation; clinically relevant; clopidogrel; commercial application; cost effective; desensitization; drug development; experience; extracellular; follow-up; immunogenicity; improved; mortality; myocardial infarct sizing; prevent; programs; research clinical testing; thrombolysis; vascular inflammation

DESCRIPTION (provided by applicant): Acute myocardial infarction is the leading cause of death in most industrialized nations. The estimated annual incidence in the US is 865,000 events, with ST-segment elevation myocardial infarction (STEMI, severe AMI) comprising an estimated 500,000 events per year. Fibrinolytic therapy is widely utilized to restore coronary blood flow due to its widespread availability to the broad cross-section of patients. The current regimen, including tissue plasminogen activator, aspirin, clopidogrel and heparin, still induces inadequate coronary reperfusion in 30-40% of patients and early thrombotic reocclusion in 5-10% patients. Moreover, successful recanalization causes detrimental reperfusion injury that accounts for up to 50% of the final size of a myocardial infarct. Net clinical adverse outcomes remain 10-12% at 30 days after treatment and 16-17% STEMI patients die during 1-year follow-up. Moreover, both morbidity and mortality are dramatically increased in patients experiencing peri-procedure bleeding. Importantly, most of the recurrent MI and major bleeding events occur in the first hours and days after treatment. Consequently, the search for more efficacious and safer acute antithrombotic agents with effective attenuation of reperfusion injury remains the "holy grail' of drug development. APT102 is an optimized human apyrase with two amino acid substitution that has significantly higher activity than the wild-type apyrases. This enzyme inhibits platelet activation and limits vascular inflammation by enzymatically hydrolyzing extracellular ADP and ATP. Adenosine is further generated by CD73 which prevents tissue damage during hypoxia and in the setting of cardiac reperfusion injury. In addition, APT102 prevents platelet desensitization and maintains homeostasis. With the Phase I award, we demonstrated that in the r-tPA induced fibrinolysis model in dogs, treatment of APT102 completely prevented re-occlusion, maintained normal blood flow, and profoundly reduced infarct size of hearts by 80% compared with clopidogrel. Meanwhile, APT102 did not prolong bleeding time, as did clopidogrel. The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel. The long-term goal is to develop APT102 as a highly effective antithrombotic and anti-inflammatory therapy with minimal bleeding risk that will profoundly improve efficacy and safety of acute treatment for AMI and other thrombotic patients. PUBLIC HEALTH RELEVANCE: The goal of this Phase II SBIR grant application is to rigorously determine whether in the coronary fibrinolysis model in dogs, APT102 promotes improved myocardial perfusion and left ventricular function with minimal bleeding compared with clopidogrel.

描述（由申请人提供）：急性心肌梗死是大多数工业化国家的主要死亡原因。在美国，估计每年发生86.5万例事件，其中st段抬高型心肌梗死（STEMI，严重AMI）估计每年发生50万例事件。纤维蛋白溶解治疗被广泛用于恢复冠状动脉血流量，因为它广泛适用于广泛的患者。目前的方案，包括组织型纤溶酶原激活剂、阿司匹林、氯吡格雷和肝素，仍然导致30-40%的患者冠状动脉再灌注不足，5-10%的患者出现早期血栓性再闭塞。此外，成功的再通会造成有害的再灌注损伤，这种损伤可占心肌梗死最终面积的50%。在治疗后30天，净临床不良结局仍为10-12%，16-17%的STEMI患者在1年随访期间死亡。此外，手术期出血患者的发病率和死亡率都显著增加。重要的是，大多数复发性心肌梗死和大出血事件发生在治疗后的头几个小时和几天。因此，寻找更有效和更安全的急性抗血栓药物，有效地减弱再灌注损伤，仍然是药物开发的“圣杯”。APT102是经过优化的人用两种氨基酸替代的APT102酶，其活性显著高于野生型APT102酶。这种酶通过酶解细胞外ADP和ATP抑制血小板活化并限制血管炎症。腺苷进一步由CD73产生，在缺氧和心脏再灌注损伤的情况下防止组织损伤。此外，APT102阻止血小板脱敏并维持体内平衡。在I期临床试验中，我们证明了在r-tPA诱导的狗纤维蛋白溶解模型中，与氯吡格雷相比，APT102治疗完全阻止了再闭塞，维持了正常的血流，并显著减少了80%的心脏梗死面积。同时，APT102和氯吡格雷均未延长出血时间。这项II期SBIR拨款申请的目的是严格确定在犬冠状动脉纤溶模型中，与氯吡格雷相比，APT102是否能改善心肌灌注和左心室功能，同时减少出血。长期目标是开发APT102作为一种高效的抗血栓和抗炎治疗，出血风险最小，将大大提高急性心肌梗死和其他血栓患者急性治疗的疗效和安全性。